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Disruption of type 2 iodothyronine deiodinase activity in cultured human glial cells by polybrominated diphenyl
Simon C Roberts1, Antonio C Bianco2, Heather M Stapleton1
1†Nicholas School of the Environment, Duke University, Durham, North Carolina 27708, United States.
Abstract:
Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disruptors and suspected neurodevelopmental toxicants. While the direct mechanisms of neurodevelopmental toxicity have not been fully elucidated, it is conceivable that alterations in thyroid hormone levels in the developing brain may contribute to these effects. Cells within the brain locally convert thyroxine (T4) to the biologically active triiodothyronine (T3) through the action of the selenodeiodinase type 2 iodothyronine deiodinase (DIO2). Previous studies have demonstrated that PBDEs can alter hepatic deiodinase activity both in vitro and in vivo; however, the effects of PBDEs on the deiodinase isoforms expressed in the brain are not well understood. Here, we studied the effects of several individual PBDEs and hydroxylated metabolites (OH-BDEs) on DIO2 activity in astrocytes, a specialized glial cell responsible for production of more than 50% of the T3 required by the brain. Primary human astrocytes and H4 glioma cells were exposed to individual PBDEs or OH-BDEs at concentrations up to 5 μM. BDE-99 decreased DIO2 activity by 50% in primary astrocyte cells and by up to 80% in the H4 cells at doses of ≥500 nM. 3-OH-BDE-47, 6-OH-BDE-47, and 5'-OH-BDE-99 also decreased DIO2 activity in cultured H4 glioma cells by 45-80% at doses of approximately 1-5 μM. Multiple mechanisms appear to contribute to the decreased DIO2 activity, including weakened expression of DIO2 mRNA, competitive inhibition of DIO2, and enhanced post-translational degradation of DIO2. We conclude that decreases in DIO2 activity caused by exposure to PBDEs may play a role in the neurodevelopmental deficits caused by these toxicants.
Insights
Polybrominated diphenyl ethers (PBDEs) disrupt thyroid hormone conversion in the brain. This study shows PBDEs reduce iodothyronine deiodinase type 2 (DIO2) activity in astrocytes, potentially causing neurodevelopmental deficits.
Area of Science:
- Neurotoxicology
- Endocrinology
- Cell Biology
Background:
- Polybrominated diphenyl ethers (PBDEs) are flame retardants with known endocrine-disrupting and neurodevelopmental toxicant properties.
- Thyroid hormones are crucial for brain development, with local conversion of thyroxine (T4) to triiodothyronine (T3) by iodothyronine deiodinase type 2 (DIO2) being vital in the brain.
- While PBDE effects on liver deiodinases are known, their impact on brain DIO2 remains unclear.
Purpose of the Study:
- To investigate the effects of individual PBDEs and their hydroxylated metabolites (OH-BDEs) on DIO2 activity in brain-representative cells.
- To elucidate the mechanisms by which PBDEs might interfere with thyroid hormone homeostasis in the brain.
Main Methods:
- Primary human astrocytes and H4 glioma cells were exposed to various PBDEs and OH-BDEs at concentrations up to 5 μM.
- DIO2 activity was measured in response to PBDE and OH-BDE exposure.
- Mechanisms including DIO2 mRNA expression, competitive inhibition, and protein degradation were assessed.
Main Results:
- BDE-99 significantly decreased DIO2 activity in both primary astrocytes (50%) and H4 cells (up to 80%) at doses ≥500 nM.
- Several hydroxylated metabolites (3-OH-BDE-47, 6-OH-BDE-47, 5'-OH-BDE-99) reduced DIO2 activity in H4 cells by 45-80% at 1-5 μM.
- Decreased DIO2 activity was linked to reduced DIO2 mRNA expression, competitive inhibition, and enhanced protein degradation.
Conclusions:
- PBDEs and their metabolites can significantly inhibit DIO2 activity in brain cells.
- This inhibition of DIO2 activity by PBDEs may contribute to the neurodevelopmental toxicity observed with these flame retardants.
- Understanding these mechanisms is crucial for assessing the risks posed by PBDE exposure during development.
